For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, as discussed in the Cellular Classification and Prognostic Variables section of this summary. Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher relapse risk, and has been used by the COG to risk-stratify patients. Similarly, end-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[32,33,34,35] Intensification of postinduction therapy for patients with high levels of end-induction MRD is under investigation by many groups. MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance.[34,36,37]
Central Nervous System (CNS) Therapy
Historically, survival rates for children with ALL did not improve until CNS-directed therapy was instituted. The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in all patients. Options for CNS-directed therapy include IT chemotherapy, CNS-penetrant systemic chemotherapy, and cranial radiation. The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurotoxicity and other late effects. The proportion of patients receiving cranial radiation has decreased significantly over time. In patients still receiving cranial radiation, the dose has been significantly reduced.
All therapeutic regimens for childhood ALL include IT chemotherapy. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (four to eight doses of IT given every 2-3 weeks), and, in certain protocols, continued throughout the maintenance phase. IT chemotherapy typically consists of either methotrexate alone or methotrexate with cytarabine and hydrocortisone. Unlike IT cytarabine, IT methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.
In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. Systemically administered drugs, such as dexamethasone, L-asparaginase, and high-dose methotrexate with leucovorin rescue, provide some degree of CNS prophylaxis. For example, in a randomized CCG study of standard-risk patients who all received the same dose and schedule of IT methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone. In a recent standard-risk ALL trial (COG-1991), lower-dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared to oral methotrexate given during each of two interim maintenance phases.[abstract]